The reason for the recrudescence of severe invasive group A streptococcal (GAS) infections remains a mystery. Has the bacteria acquired new virulence, or has the host immune defense mechanism been altered? These mutually non-exclusive possibilities can be examined by investigating specific host and pathogen factors that are likely to contribute to disease pathogenesis. Streptococcal pyrogenic exotoxins (Spes), which are superantigens (SAgs), induce potent inflammatory responses, and are believed to play a pivotal role in these diseases. However, the ability of the same GAS strain to cause disease of varying severity in different hosts, suggests that host factors play a crucial role in modulating disease severity. Individuals with invasive GAS infections can be classified into a group with severe (hypotension & organ failure) and nonsevere (no hypotension and no organ failure) invasive disease. Differences in disease presentation may relate to different phenotypic expression of Spes/SAgs in genotypically identical strains, to differences in prior exposure of the host to Spes/SAgs (indicated by the presence of protective immunity), or to inborn variation in responsiveness when exposed to Spes/SAgs. Our hypothesis is that the interaction of pathogen and host factors contribute to the severity of invasive GAS infections. Our main objective is to identify immunogenetic host factors that are important in modulating the severity of symptoms in patients with invasive disease. In order to be able to identify these host factors, it is necessary to study a cohort of patients with invasive disease that was caused by same strain of GAS. To achieve this goal we will: (1) Identify a cohort of severe and nonsevere invasive cases caused by genotypically identical M1T1 strains; (2) Test the hypothesis that genotypically identical M1T1 strains isolated from severe or nonsevere invasive cases differ in the in vitro expression of specific virulence factors that are likely to contribute to the systemic manifestation of the disease; (3) Determine whether the in vivo inflammatory response differs in patients with severe and nonsevere invasive infections caused by identical strains; and (4) Determine whether the following host factors are important in modulating disease severity: serum neutralizing antibodies, HLA class II allotype, and baseline TCR V beta frequency distributions affecting cytokine responses to the infecting isolate. Genotypically identical M1T1 strains (from severe and nonsevere cases) will be analyzed for differences in phenotypic production of immunogenic factors, namely Spe/SAgs. Severe and nonsevere invasive cases who were infected with these isolates will be investigated to determine differences in their in vivo inflammatory cytokine responses during the infection, and identify immunogenetic factors that may be responsible for regulating the magnitude of the inflammatory response and modulating disease severity.